D.A.-1
The Diels-Alder Reaction
Otto Diels and his pupil Kurt Alder received the Nobel Prize in 1950 for their discovery and work on the
reaction that bears their names. Its great usefulness lies in its high yield and high stereospecificity. A
cycloaddition reaction, it involves the 1,4-addition of a conjugated diene in the s-cis-conformation to an
alkene in which two new sigma bonds are formed from two pi bonds.
new sigma
bonds
s-trans
s-cis
The adduct is a six-membered ring alkene. The diene can have the two conjugated bonds contained
within a ring system as with cyclopentadiene or cyclohexadiene, or the molecule can be an acyclic diene
that must be in the cis conformation about the single bond before reaction can occur.
H
C
C
H3C
O
H
O
H3C
CH3
H
CH3
H
H
CH3
C O
H
CH3
The reaction works best when there is a marked difference between the electron densities in the diene
and the alkene with which it reacts, the dienophile. Usually the dienophile has electron-attracting groups
attached to it while the diene is electron rich, e.g., as in the reaction of methyl vinyl ketone with 1,3butadiene.
C
butadiene
CH3
C
O
methyl vinyl
ketone
CH3
O
Retention of the configurations of the reactants in the products implies that both new sigma bonds are
formed almost simultaneously. If not, then the intermediate with a single new bond could rotate about that
bond before the second sigma bond is formed, thus destroying the stereospecificity of the reaction.
H
H
CO2CH3
H
CO2CH3
CO2CH3
H
CO2CH3
CO2CH3
H3CO2C
cis-isomer
D.A.-2
This does not happen:
H
H
H
CO2CH3
CO2CH3
CO2CH3
H
H
H3CO2C
CO2CH3
CO2CH3
H
H
CO2CH3
CO2CH3
H3CO2C
H3CO2C
H
tans-isomer
This reaction is not polar in that no charged intermediates are formed. Neither is it radical because no
unpaired electrons are involved. It is instead known as a concerted reaction. or one in which several
bonds in the transition state are simultaneously made and broken. When a cyclic diene and a cyclic
dienophile react with each other as in the present reaction, more than one stereoisomer may be formed.
The isomer that predominates is the one which involves maximum overlap of pi electrons in the transition
state. The transition state for the formation of the endo-isomer in the present reaction involves a sandwich
with the diene directly above the dienophile. To form the exo-isomer the diene and dienophile would need
to be arranged in a stair-step fashion.
The Diels-Alder reaction has been used extensively in the synthesis of complex natural products because
it is possible to exploit the formation of a number of chiral centers in one reaction and also the
regioselectivity of the reaction. For example, the first step in R. B. Woodward's synthesis of cortisone was
the formation of a Diels-Alder adduct.
O
CH3
Woodwards diels-Alder adduct
H3CO
O
H
But the reaction is also subject to steric hindrance, especially when the adifference between the electronwithdrawing and donating characters of the two reactants is not great. When Woodward tried to
synthesize cantharidin, the active ingredient in Spanish fly, by the Diels-Alder condensation of furan with
dimethylmaleic anhydride. the reaction did not work. The reaction possesses -∆ V* (it proceeds with a net
decrease in volume). High pressure should overcome this problem. but this reaction will not proceed even
2
at 600.000 lb/in . Cantharidin is a powerful vesicant (blister-former).
D.A.-3
O
O
O
Cantharidin
CH3 O
H3C
Woodward and Roald Hoffmann, Nobel prize winners for their work, formulated the theoretical rules
involving the correlation of orbital symmetry, which govern the Diels-Alder and other electrocyclic
reactions.
Cyclopentadiene is obtained from the light oil from coal tar distillation but exists as the stable dimer,
dicyclopentadiene, which is the Diels-Alder adduct from two molecules of the diene. Thus. generation of
cyclopentadiene by pyrolysis of the dimer represents a reverse Diels-Alder reaction. In the Diels-Alder
addition of cyclopentadiene and maleic anhydride the two molecules approach each other in the
orientation shown in the drawing above. as this orientation provides maximal overlap of π-bonds of the
two reactants and favors formation of an initial π-complex and then the final endo-product.
Dicyclopentadiene also has the endo-configuration.
Experiments
Gas chromatography reveals that cyclopentadiene is 8% dimerized in 4 hours and 50% dimerized in 24
hours when stored at room temperature. Therefore, it should be kept on ice and used as soon as
possible.
D.A.-4
1. Cracking of Dicyclopentadiene
We’ll do this for you.
2. cis-Norbornene-5,6-endo-dicarboxylic Anhydride
O
+
O
O
O
O
O
maleic anhydride
anhydride
mp 53oC, MW 98.06
MW 164.16
Place 3 g (? moles) of maleic anhydride in a 125 mL Erlenmeyer flask and dissolve the anhydride in 10
mL of ethyl acetate by gentle heating on a hot plate. Add 10 mL of ligroin (bp 60-90°C), cool the solution
to 0°C in an ice bath, and leave it in the bath (some material may crystallize).
Measure 3 mL of cyclopentadiene (? moles), and add it to the ice-cold solution of maleic anhydride. Swirl
the solution in the ice bath for a few minutes until the exothermic reaction is over and the adduct
separates as a white solid. Then, carefully (gently) heat the mixture on a hot plate until the solid is all
dissolved. Do not boil off all of your solvent. If moisture has gotten into your reaction, a little of the
corresponding, insoluble, diacid will need to be removed by filtration of the hot solution. Place the flask on
a cork ring and allow to cool slowly. If you let the solution stand undisturbed, you may be rewarded with a
beautiful display of crystal formation. mp ~165°C; typical yield is ~4.1 g.
Dispose of your crystallization solvent in the waste container provided.
3. cis-Norbornene-5,6-endo-dicarboxylic Acid
O
+
H2O
O
O
O
OH
O OH
diacid
For the preparation of the endo, cis-diacid, place 2 g (? moles) of the anhydride from part 2 in 25 mL of
deionized water. Heat the mixture with swirling, until the contents boil. Continue to heat the boiling
mixture until all of the material dissolves (an oil substance may initially form, but will eventually completely
dissolve). Allow the solution to cool slowly. Since the diacid has a tendency to remain in a supersaturated
solution, let the solution cool to room temperature and, if needed, gently scratch the flask at the water/air
interface inside the flask. Let crystallization proceed spontaneously to give large needles, then cool the
solution on ice, and filter to isolate the product. mp ~180°C, typical yield is ~2 g.
Dispose of your aqueous solution by flushing down the drain.
D.A.-5
Questions
1. Draw the products of the following reactions:
CN
a.
+
NC
CO2CH3
OCH3
+
b.
H3CO2C
CO2CH2CH3
c.
O
+
CH3
2. Draw the starting materials for the following reactions:
CH3
CN
a.
CN
H3C
b.
c.
CO2CH3
CH3